Bone med: Mixed blessing for breast cancer

U. SHEFFIELD (UK) — A drug commonly used to protect bone boosts disease-free survival in postmenopausal breast cancer patients—but may have an adverse effect on younger women.

The findings, published in the New England Journal of Medicine, shed new light on the role bones may play in the progression of the disease.

Bisphosphonate drugs, like zoledronic acid, are used mainly to treat osteoporosis but may also be given to breast cancer patients to protect against the effects of secondary bone cancer.


The trial, which started in 2003, involved 3,360 women with early breast cancer from 174 centers in the UK, Australia, Spain, Ireland, Portugal, Taiwan, and Thailand. Patients were randomized to receive standard chemotherapy and/or endocrine therapy (hormone therapy) for their breast cancer, to try and prevent recurrence or spread of the disease, with or without zoledronic acid.

Contrary to previous studies, there was no significant difference in disease-free or overall survival between patients who received zoledronic acid and those that did not, looking at the study population as a whole.

However, the addition of zoledronic acid did bring significant benefits to postmenopausal women.

Those women had significantly improved disease-free and overall survival—the overall survival rate at five years was 85 percent compared to 79 percent for women who did not receive zoledronic acid.

The benefit was independent of the characteristics of the disease as defined by the stage of the tumor, estrogen receptor status, and lymph node involvement. For all other patients, overall five year survival was similar at 86 percent in the zoledronic acid group and 85 percent in the control group.

Most surprisingly, it was the recurrence rates outside bone that were most profoundly affected by the zoledronic acid with clear benefit in the postmenopausal women but a possible adverse effect in younger women.

The relative risk for developing metastases outside bone during treatment with zoledronic acid was approximately halved in the postmenopausal women compared with the younger patients.

The effects on metastasis and recurrence outside bone suggests that the bone marrow is an important sanctuary for tumor cells which can be activated after many years of dormancy. With help from bone marrow stem cells, these previously dormant tumor cells may then spread via the blood stream to set up metastases at other sites.

Other studies in postmenopausal women and younger women given treatment to induce menopause with hormone sensitive breast cancer have also indicated benefit for zoledronic acid in early breast cancer.

The trial is the first study to evaluate the use of zoledronic acid in a broad range of patients.

“The results have shown that zoledronic acid should not be used routinely for the treatment of early breast cancer,” says Robert Coleman, a professor at the University of Sheffield.

“However, for those with low levels of female hormones, due either to natural aging or specific treatments to induce menopause, the approach appears very promising as more women go on to rid themselves of the disease.

“Our findings could mean a major new treatment approach for the tens of thousands of women in the UK who develop breast cancer. We are now investigating the hormone levels in blood and the biology of the breast tumors in samples donated by the AZURE patients to help us better understand the reasons behind our results.”

Helen Marshall, Principal Statistician from the University of Leeds´ Clinical Trials Research Unit (CTRU), says: “The statistics of this analysis are complex and the results need to be interpreted with a degree of caution. The size and significance of the difference by menopausal status suggests that this finding is genuine, but we will need to carry out further studies to substantiate this exciting result.”

The project was funded by a grant from the pharmaceutical company Novartis.

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